Validity of the Institut Mutualiste Montsouris classification system for robotic liver resection.

BACKGROUND: The Institut Mutualiste Montsouris (IMM) classification system is one of several widely accepted difficulty scoring systems for laparoscopic liver resections. Nothing is yet known about the applicability of this system for robotic liver resections. METHODS: We conducted a retrospective review of 359 patients undergoing robotic hepatectomies between 2016 and 2022. Resections were classified into low, intermediate, and high difficulty level. Data were analyzed utilizing ANOVA of repeated measures, 3 x 2 contingency tables, and area under the receiving operating characteristic (AUROC) curves. Data are presented as median (mean ± SD). RESULTS: Of the 359 patients, 117 were classified as low-difficulty level, 92 as intermediate, and 150 as high. The IMM system correlates well with tumor size (p = 0.002). The IMM system was a strong predictor of intraoperative outcomes including operative duration (p<0.001) and estimated blood loss (EBL) (p<0.001). The IMM system also showed a strong calibration for predicting an open conversion (AUC=0.705) and intraoperative complications (AUC=0.79). In contrast, the IMM system was a poor predictor of postoperative complications, mortality, and readmission. CONCLUSION: The IMM system provides a strong correlation with intraoperative, but not postoperative outcomes. A dedicated difficulty scoring system should be developed for robotic hepatectomy.

Hypoxia-ischemia-mediated effects on neurodevelopmentally regulated cold-shock proteins in neonatal mice under strict temperature control.

BACKGROUND: Neonates have high levels of cold-shock proteins (CSPs) in the normothermic brain for a limited period following birth. Hypoxic-ischemic (HI) insults in term infants produce neonatal encephalopathy (NE), and it remains unclear whether HI-induced pathology alters baseline CSP expression in the normothermic brain. METHODS: Here we established a version of the Rice-Vannucci model in PND 10 mice that incorporates rigorous temperature control. RESULTS: Common carotid artery (CCA)-ligation plus 25 min hypoxia (8% O2) in pups with targeted normothermia resulted in classic histopathological changes including increased hippocampal degeneration, astrogliosis, microgliosis, white matter changes, and cell signaling perturbations. Serial assessment of cortical, thalamic, and hippocampal RNA-binding motif 3 (RBM3), cold-inducible RNA binding protein (CIRBP), and reticulon-3 (RTN3) revealed a rapid age-dependent decrease in levels in sham and injured pups. CSPs were minimally affected by HI and the age point of lowest expression (PND 18) coincided with the timing at which heat-generating mechanisms mature in mice. CONCLUSIONS: The findings suggest the need to determine whether optimized therapeutic hypothermia (depth and duration) can prevent the age-related decline in neuroprotective CSPs like RBM3 in the brain, and improve outcomes during critical phases of secondary injury and recovery after NE. IMPACT: The rapid decrease in endogenous neuroprotective cold-shock proteins (CSPs) in the normothermic cortex, thalamus, and hippocampus from postnatal day (PND) 11-18, coincides with the timing of thermogenesis maturation in neonatal mice. Hypoxia-ischemia (HI) has a minor impact on the normal age-dependent decline in brain CSP levels in neonates maintained normothermic post-injury. HI robustly disrupts the expected correlation in RNA-binding motif 3 (RBM3) and reticulon-3 (RTN3). The potent neuroprotectant RBM3 is not increased 1-4 days after HI in a mouse model of neonatal encephalopathy (NE) in the term newborn and in which rigorous temperature control prevents the manifestation of endogenous post-insult hypothermia.

Patient satisfaction and cost savings analysis of the telemedicine program within a neuro-oncology department.

PURPOSE: Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. METHODS: 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. RESULTS: Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. CONCLUSION: Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.

The Presence of a Psychiatric Condition is Associated With Undergoing Hip Arthroscopy for Femoroacetabular Impingement: A Matched Case-Controlled Study.

BACKGROUND: We sought to examine the association between having a psychiatric condition and undergoing hip arthroscopy for femoroacetabular impingement (FAI). METHODS: A matched case-control study was performed to control for age and gender. All patients over 16 years of age with FAI treated with hip arthroscopy by a single surgeon were randomly matched to a patient of the same age and gender undergoing knee arthroscopy for any diagnosis other than infection by the same surgeon during the same period. Conditional logistic regression was used to compare the odds of having a psychiatric condition between groups. RESULTS: Fifty-one matched pairs of patients undergoing hip and knee arthroscopy were identified. Each group contained 35 females (69%) and had a mean age of 33.6 years. Of the 51 hip arthroscopy cases, 23 (45.1%) had a psychiatric condition. Of the 51 knee arthroscopy controls, 11 (21.6%) had a psychiatric condition. Patients undergoing hip arthroscopy were statistically significantly more likely to have a psychiatric condition compared to patients undergoing knee arthroscopy with an odds ratio of 3.4 (95% confidence interval 1.3-9.2, P < .01). CONCLUSION: There was a strong association between having a psychiatric condition and undergoing hip arthroscopy for FAI. More research should be done investigating psychiatric conditions among patients with FAI and whether this association can identify strategies to optimize patient outcomes.

Immunomodulatory spherical nucleic acids.

Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.

Understanding ion-transfer reactions in silver electrodissolution and electrodeposition from first-principles calculations and experiments.

The electrified aqueous/metal interface is critical in controlling the performance of energy conversion and storage devices, but an atomistic understanding of even basic interfacial electrochemical reactions challenges both experiment and computation. We report a combined simulation and experimental study of (reversible) ion-transfer reactions involved in anodic Ag corrosion/deposition, a model system for interfacial electrochemical processes generating or consuming ions. With the explicit modeling of the electrode potential and a hybrid implicit-explicit solvation model, the density functional theory calculations produce free energy curves predicting thermodynamics, kinetics, partial charge profiles, and reaction trajectories. The calculated (equilibrium) free energy barriers (0.2 eV), and their asymmetries, agree with experimental activation energies (0.4 eV) and transfer coefficients, which were extracted from temperature-dependent voltage-step experiments on Au-supported, Ag-nanocluster substrates. The use of Ag nanoclusters eliminates the convolution of the kinetics of Ag+(aq.) generation and transfer with those of nucleation or etch-pit formation. The results indicate that the barrier is controlled by the bias-dependent competition between partial solvation of the incipient ion, metal-metal bonding, and electrostatic stabilization by image charge, with the latter two factors weakened by stronger positive biases. We also report simulations of the bias-dependence of defect generation relevant to nucleating corrosion by removing an atom from a perfect Ag(100) surface, which is predicted to occur via a vacancy-adatom intermediate. Together, these experiments and calculations provide the first validated, accurate, molecular model of the central steps that govern the rates of important dissolution/deposition reactions broadly relevant across the energy sciences.

Examining surgeon stress in robotic and laparoscopic surgery.

Robotic surgery may decrease surgeon stress compared to laparoscopic. To evaluate intraoperative surgeon stress, we measured salivary alpha-amylase and cortisol. We hypothesized robotic elicited lower increases in surgeon salivary amylase and cortisol than laparoscopic. Surgical faculty (n = 7) performing laparoscopic and robotic operations participated. Demographics: age, years in practice, time using laparoscopic vs robotic, comfort level and enthusiasm for each. Operative data included operative time, WRVU (surgical "effort"), resident year. Saliva was collected using passive drool collection system at beginning, middle and end of each case; amylase and cortisol measured using ELISA. Standard values were created using 7-minute exercise (HIIT), collecting saliva pre- and post-workout. Linear regression and Student's t test used for statistical analysis; p values < 0.05 were significant. Ninety-four cases (56 robotic, 38 laparoscopic) were collected (April-October 2022). Standardized change in amylase was 8.4 ± 4.5 (p < 0.001). Among operations, raw maximum amylase change in laparoscopic and robotic was 23.4 ± 11.5 and 22.2 ± 13.4; raw maximum cortisol change was 44.21 ± 46.57 and 53.21 ± 50.36, respectively. Values normalized to individual surgeon HIIT response, WRVU, and operative time, showing 40% decrease in amylase in robotic: 0.095 ± 0.12, vs laparoscopic: 0.164 ± 0.16 (p < 0.02). Normalized change in cortisol was: laparoscopic 0.30 ± 0.44, robotic 0.22 ± 0.4 (p = NS). On linear regression (p < 0.001), surgeons comfortable with complex laparoscopic cases had lower change in normalized amylase (p < 0.01); comfort with complex robotic was not significant. Robotic may be less physiologically stressful, eliciting less increase in salivary amylase than laparoscopic. Comfort with complex laparoscopic decreased stress in robotic, suggesting laparoscopic experience is valuable prior to robotic.

Emerging ideas: Novel 3-D quantification and classification of cam lesions in patients with femoroacetabular impingement.

BACKGROUND: Femoroacetabular impingement (FAI) can lead to labral injury, osseous changes, and even osteoarthritis. The literature contains inconsistent definitions of the alpha angle and other nonthree-dimensional (3-D) radiographic measures. We present a novel approach to quantifying cam lesions in 3-D terms. Our method also can be used to develop a classification system that describes the exact location and size of cam lesions. QUESTIONS/HYPOTHESES: We asked whether automated quantification of CAM lesions based on CT data is a reasonable way to detect CAM lesions and whether they may be classified based on location. METHOD OF STUDY: We developed a method to quantify femoral head cam lesions using 3-D modeling of CT scans. By segmenting raw DICOM data, we can determine the distance from the cam lesion's surface points to the centroid of the femoral head to quantify the mean bump height, volume, and location. The resulting 3-D femoral and acetabular models will be analyzed with custom software. We then will quantify the cam lesion with 3-D parameters using a modified zoning method. The mean bump height, volume, and location on the clock face, and relative zoning will be calculated. Zonal differences will be statistically analyzed. To assess the ability of this method to predict arthroscopic findings, we will obtain preoperative CT scans for 25 patients who undergo hip arthroscopy for FAI. We will compare measurements with the method with our measurements from arthroscopy. The clinical implications of our method's measurements then will be reviewed and refined for future prospective studies. SIGNIFICANCE: We present a novel approach that can quantify a cam lesion's location and size. This method will be used to provide guidelines for the exact amount of bony resection needed from a specific location of the proximal femur. There is also potential to develop software for ease of use so this method can be more widely applied.

Age-related differences in radiographic parameters for femoroacetabular impingement in hip arthroplasty patients.

PURPOSE: To compare the prevalence of femoroacetabular impingement (FAI) radiographic findings between patients aged younger than 50 years and those aged 50 years or older who underwent total hip arthroplasty. METHODS: Total hip arthroplasty patients aged younger than 50 years and those aged 50 years or older were identified retrospectively from a facility medical record database. Fifty patients from each group were randomly selected, and preoperative radiographs were collected. Dysplastic, inflammatory, post-traumatic, and osteonecrosis patients were excluded. Radiographs were evaluated for FAI-specific findings. Intraobserver and interobserver reliability was evaluated with κ statistics for categorical variables and intraclass correlation coefficients for continuous variables. An independent t test was used to compare continuous variables, χ(2) analysis was used for discrete variables, and a z ratio was used to analyze proportions. RESULTS: The mean age between the subgroups of patients aged younger than 50 years and those aged 50 years or older (43 years and 68 years, respectively) was significantly different (P < .05). Findings in the subgroup aged younger than 50 years included significantly more men (P < .001), decreased lateral joint space with maintained medial joint space (P < .05), significantly greater alpha angle on both the anteroposterior view and the frog-leg lateral view (P < .05), significantly higher Tönnis and Sharp angles (P < .01), and significantly lower center-edge angle (P < .001). CONCLUSIONS: This retrospective case series shows an increased prevalence of FAI findings (specifically cam pathology) in a patient population aged younger than 50 years undergoing total hip arthroplasty when compared with a cohort aged 50 years or older. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Safety and feasibility of a novel bi-directional portal vein access kit during transjugular intrahepatic portosystemic shunt creation.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) creation remains as one of the more technically challenging endovascular procedures. Portal vein access from the hepatic vein often requires multiple needle passes, which increases procedure times, risk of complications, and radiation exposure. With its bi-directional maneuverability, the Scorpion X access kit may be a promising tool for easier portal vein access. However, the clinical safety and feasibility of this access kit has yet to be determined. MATERIALS AND METHODS: In this retrospective study, 17 patients (12 male, average age 56.6 ± 9.01) underwent TIPS procedure using Scorpion X portal vein access kits. The primary endpoint was time taken to access the portal vein from the hepatic vein. The most common indications for TIPS were refractory ascites (47.1%) and esophageal varices (17.6%). Radiation exposure, total number of needle passes, and intraoperative complications were recorded. Average MELD Score was 12.6 ± 3.39 (range: 8-20). RESULTS: Portal vein cannulation was successfully achieved in 100% of patients during intracardiac echocardiography-assisted TIPS creation. Total fluoroscopy time was 39.31 ± 17.97 min; average radiation dose was 1036.76 ± 644.15 mGy, while average contrast dose was 120.59 ± 56.87 mL. The average number of passes from the hepatic vein to the portal vein was 2 (range: 1-6). Average time to access the portal vein once the TIPS cannula was positioned in the hepatic vein was 30.65 ± 18.64 min. There were no intraoperative complications. CONCLUSIONS: Clinical utilization of the Scorpion X bi-directional portal vein access kit is both safe and feasible. Utilizing this bi-directional access kit resulted in successful portal vein access with minimal intraoperative complications. LEVEL OF EVIDENCE: Retrospective cohort.

Analysis of Clinical Outcomes After Robotic Hepatectomy Applying the Western-Model Southampton Laparoscopic Difficulty Scoring System. An Experience From a Tertiary US Hepatobiliary Center.

BACKGROUND: Identification of resections with high risk of intraoperative complications is critical in guiding case selection for minimally invasive liver surgery. Several Japanese and European difficulty scoring systems have been proposed for laparoscopic liver surgery. However, the applicability of these systems for robotic liver resections has not been fully investigated. This study considers the Southampton system and examines its validity when applied to robotic hepatectomies. METHODS: We undertook a retrospective review of 372 patients who underwent robotic hepatectomies for various indications between 2013 and 2022. Of these patients, 63 operations were classified as low risk, 91 as moderate risk, 198 as high risk and 20 as extremely high risk based on Southampton criteria. Patient outcomes were compared by utilizing an ANOVA of repeated measures. Data are presented as median (mean ± SD). RESULTS: The Southampton difficulty scoring system was a strong predictor of intraoperative variables including tumor size, operative duration, estimated blood loss (EBL), and incidence of major vs minor resection (all P < .0001). In contrast, the Southampton system was a weaker predictor of postoperative outcomes including 30-day mortality (P = .15), length of stay (P = .13), and readmissions within 30 days (P = .38). CONCLUSION: The Southampton difficulty scoring system is a valid system for classifying robotic liver resections and is a strong predictor of intraoperative outcomes. However, the system was found to be a weaker predictor of postoperative outcomes. This finding may suggest the need for proposal of a new difficulty scoring system for robotic hepatectomies.

Predictors of endobronchial forceps utilization for inferior vena cava filter retrieval: when snare retrieval fails.

BACKGROUND: Endobronchial forceps are commonly used for complex IVC filter removal and after initial attempts at IVC filter retrieval with a snare have failed. Currently, there are no clear guidelines to help distinguish cases where primary removal should be attempted with standard snare technique or whether attempts at removal should directly be started with forceps. This study is aimed to identify clinical and imaging predictors of snare failure which necessitate conversion to endobronchial forceps. METHODS: Retrospective analysis of 543 patients who underwent IVC filter retrievals were performed at three large quaternary care centers from Jan 2015 to Jan 2022. Patient demographics and IVC filter characteristics on cross-sectional images (degree of tilt, hook embedment, and strut penetration, etc.) were reviewed. Binary multivariate logistic regression was used to identify predictors of IVC filter retrieval where snare retrieval would fail. RESULTS: Thirty seven percent of the patients (n = 203) necessitated utilization of endobronchial forceps. IVC filter hook embedment (OR:4.55; 95%CI: 1.74-11.87; p = 0.002) and strut penetration (OR: 56.46; 95% CI 20.2-157.7; p = 0.001) were predictors of snare failure. In contrast, total dwell time, BMI, and degree of filter tilt were not associated with snare failure. Intraprocedural conversion from snare to endobronchial forceps was significantly associated with increased contrast volume, radiation dose, and total procedure times (p < 0.05). CONCLUSION: IVC filter hook embedment and strut penetration were predictors of snare retrieval failure. Intraprocedural conversion from snare to endobronchial forceps increased contrast volume, radiation dose, and total procedure time. When either hook embedment or strut penetration is present on pre-procedural cross-sectional images, IVC filter retrieval should be initiated using endobronchial forceps. LEVEL OF EVIDENCE: Level 3, large multicenter retrospective cohort.

v-SNARE cellubrevin is required for basolateral sorting of AP-1B-dependent cargo in polarized epithelial cells.

The epithelial cell-specific adaptor complex AP-1B is crucial for correct delivery of many transmembrane proteins from recycling endosomes to the basolateral plasma membrane. Subsequently, membrane fusion is dependent on the formation of complexes between SNARE proteins located at the target membrane and on transport vesicles. Although the t-SNARE syntaxin 4 has been localized to the basolateral membrane, the v-SNARE operative in the AP-1B pathway remained unknown. We show that the ubiquitously expressed v-SNARE cellubrevin localizes to the basolateral membrane and to recycling endosomes, where it colocalizes with AP-1B. Furthermore, we demonstrate that cellubrevin coimmunoprecipitates preferentially with syntaxin 4, implicating this v-SNARE in basolateral fusion events. Cleavage of cellubrevin with tetanus neurotoxin (TeNT) results in scattering of AP-1B localization and missorting of AP-1B-dependent cargos, such as transferrin receptor and a truncated low-density lipoprotein receptor, LDLR-CT27. These data suggest that cellubrevin and AP-1B cooperate in basolateral membrane trafficking.

Effects of Lovastatin on Brain Cancer Cells.

Although brain tumors occur less frequently than other forms of cancer, they have one of the bleakest prognoses with low survival rates. The conventional treatment for brain tumors includes surgery, radiotherapy, and chemotherapy. However, resistance to treatment remains a problem with recurrence shortly following. The resistance to treatment may be caused by cancer stem cells (CSCs), a subset of brain tumor cells with the affinity for self-renewal and differentiation into multiple cell lineages. An emerging approach to targeting CSCs in brain tumors is through repurposing the lipid-lowering medication, lovastatin. Lovastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that impacts the mevalonate pathway. The inhibition of intermediates in the mevalonate pathway affects signaling cascades and oncogenes associated with brain tumor stem cells (BTSC). In this review, we show the possible mechanisms where lovastatin can target BTSC for different varieties of malignant brain tumors.

Relativistic Orbital-Optimized Density Functional Theory for Accurate Core-Level Spectroscopy.

Core-level spectra of 1s electrons of elements heavier than Ne show significant relativistic effects. We combine advances in orbital-optimized density functional theory (OO-DFT) with the spin-free exact two-component (X2C) model for scalar relativistic effects to study K-edge spectra of third period elements. OO-DFT/X2C is found to be quite accurate at predicting energies, yielding a ∼0.5 eV root-mean-square error versus experiment with the modern SCAN (and related) functionals. This marks a significant improvement over the >50 eV deviations that are typical for the popular time-dependent DFT (TDDFT) approach. Consequently, experimental spectra are quite well reproduced by OO-DFT/X2C, sans empirical shifts for alignment. OO-DFT/X2C combines high accuracy with ground state DFT cost and is thus a promising route for computing core-level spectra of third period elements. We also explored K and L edges of 3d transition metals to identify limitations of the OO-DFT/X2C approach in modeling the spectra of heavier atoms.

Lovastatin Inhibits RhoA to Suppress Canonical Wnt/ß-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer.

Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APCmin mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/ß-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/ß-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/ß-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit ß-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/ß-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.

Targeting the IL-17 Receptor Using Liposomal Spherical Nucleic Acids as Topical Therapy for Psoriasis.

The activation of T helper 17 signaling plays a critical role in psoriasis pathogenesis, and systemically-administered IL-17 inhibitors are highly effective therapy for moderate-to-severe disease. We generated topically-delivered gene-regulating nanoconstructs, comprised of spherically-arrayed antisense DNA (liposomal spherical nucleic acids [L-SNAs]), which are able to penetrate human skin to knock down cutaneous gene targets. Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin. Il17ra L-SNAs reduced the modified PASI by 74% versus controls and decreased epidermal thickness by 56%. Il17ra L-SNA reduced Il17ra protein expression by 75% and significantly decreased the mRNA expression of psoriasis markers, including Defb4, Il17c, S100a7, Pi3, Krt16, and Tnfa versus scrambled spherical nucleic acid (Scr SNA) controls. A human IL17RA L-SNA penetrates 3-dimensional cultures and normal human explants to knock down IL17RA mRNA by 63% and 66%, respectively. After topical application to psoriatic 3-dimensional rafts, anti-human IL17RA L-SNAs reduced the expression of IL17RA (by 72%) and the IL-17-induced genes IL17C (by 85%), DEFB4 (by 83%), TNFA (by 77%), and PI3 (by 65%) versus scrambled L-SNA and vehicle controls (all P < 0.001). Taken together, these data suggest that targeted suppression of IL17RA is a promising new topical treatment strategy for psoriasis.

HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations.

Recruitment of the histone deacetylase (HDAC)-associated Sin3 corepressor is an obligatory step in many eukaryotic gene silencing pathways. Here we show that HBP1, a cell cycle inhibitor and regulator of differentiation, represses transcription in a HDAC/Sin3-dependent manner by targeting the mammalian Sin3A (mSin3A) PAH2 domain. HBP1 is unrelated to the Mad1 repressor for which high-resolution structures in complex with PAH2 have been described. We show that like Mad1, the HBP1 transrepression domain binds through a helical structure to the hydrophobic cleft of mSin3A PAH2. Notably, the HBP1 helix binds PAH2 in a reversed orientation relative to Mad1 and, equally unexpectedly, this is correlated with a chain reversal of the minimal Sin3 interaction motifs. These results not only provide insights into how multiple, unrelated transcription factors recruit the same coregulator, but also have implications for how sequence similarity searches are conducted.

Complications associated with anterior shoulder instability repair.

Anterior shoulder instability is a common orthopaedic problem, and the surgical treatment, both open and arthroscopic, has been shown to effectively restore stability and prevent recurrence. However, despite success with these surgical techniques, there are several clinically relevant complications associated with both open and arthroscopic techniques for anterior shoulder stabilization. These complications can be subdivided into preoperative, intraoperative, and postoperative and include entities such as nerve injury, chondrolysis, incomplete treatment of associated lesions, and subscapularis dysfunction. When they occur, complications may significantly impact patient outcomes and function. Therefore, surgeon awareness and identification of the factors associated with these complications may help prevent occurrence. Although failure of instability repair can be classified as a complication of surgery, it requires an entirely separate discussion and is therefore not addressed in this article. Because most of the previously published studies on anterior shoulder instability have emphasized surgical technique and clinical outcomes, the purpose of this article is to define the complications associated with anterior instability repair and provide recommendations on techniques that may be used to help avoid them.

Triad of cartilage restoration for unicompartmental arthritis treatment in young patients: meniscus allograft transplantation, cartilage repair and osteotomy.

Arthritis treatment in young patients remains a challenge. Joint replacement surgery offers excellent pain relief but is controversial with this age group because of long-term wear and loosening. Recently, biological reconstructive techniques have become available to improve traditional treatment methods such as osteotomies. We present our experience with a technique for combined meniscal transplantation, chondral repair, and osteotomy in 7 patients presenting with a constellation of meniscal deficiency, focal arthritis, and malalignment. Patients underwent concurrent or staged meniscal transplantation, cartilage repair, and osteotomy. Evaluation included the International Knee Documentation Committee (IKDC) score, Knee injury and Osteoarthritis Outcome Score (KOOS), and Short Form-12 and Lysholm scales. At average follow-up of 24 months, patients experienced significant improvements in the IKDC, Lysholm, and KOOS functional scores. Six of 7 patients were able to return to unrestricted activities; 1 patient experienced mild pain with high-impact activities. Combined treatment with meniscal transplantation, cartilage repair, and osteotomy demonstrated promising clinical results of unicompartmental arthritis treatment in young patients.